title: Neutrophils contribute to inflammatory lymphangiogenesis by increasing VEGF-A bioavailability and secreting VEGF-D.
abstract: Lymphangiogenesis is an important physiological response to inflammatory insult, acting to limit inflammation. Macrophages, dendritic cells, and lymphocytes are known to drive lymphangiogenesis. In this study, we show that neutrophils recruited to sites of inflammation can also coordinate lymphangiogenesis. In the absence of B cells, intranodal lymphangiogenesis induced during prolonged inflammation as a consequence of immunization is dependent on the accumulation of neutrophils. When neutrophils are depleted in wild-type mice developing skin inflammation in response to immunization or contact hypersensitization, lymphangiogenesis is decreased and local inflammation is increased. We demonstrate that neutrophils contribute to lymphangiogenesis primarily by modulating vascular endothelial growth factor (VEGF)-A bioavailability and bioactivity and, to a lesser extent, secreting VEGF-D. We further show that neutrophils increased VEGF-A bioavailability and bioactivity via the secretion of matrix metalloproteinases 9 and heparanase. Together, these findings uncover a novel function for neutrophils as organizers of lymphangiogenesis during inflammation.
authors.affiliation: Department of Microbiology, Immunology Programme, Yong Loo Lin School of Medicine, National University of Singapore; and.
authors.forename: Kar Wai
authors.initials: KW
authors.lastname: Tan
authors.forename: Shu Zhen
authors.initials: SZ
authors.lastname: Chong
authors.forename: Fiona H S
authors.initials: FH
authors.lastname: Wong
authors.forename: Maximilien
authors.initials: M
authors.lastname: Evrard
authors.forename: Sandra Min-Li
authors.initials: SM
authors.lastname: Tan
authors.forename: Jo
authors.initials: J
authors.lastname: Keeble
authors.forename: D M
authors.initials: DM
authors.lastname: Kemeny
authors.forename: Lai Guan
authors.initials: LG
authors.lastname: Ng
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Abastado
authors.forename: Véronique
authors.initials: V
authors.lastname: Angeli
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003872:Dermatitis / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D005260:Female; D005966:Glucuronidase / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D042583:Lymphangiogenesis / Q000276:immunology / Q000502:physiology*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009504:Neutrophils / Q000276:immunology / Q000473:pathology / Q000502:physiology*; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D042643:Vascular Endothelial Growth Factor D / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism; D000099175:Heparanase
chemical_list: D005966:Glucuronidase; D020780:Matrix Metalloproteinase 9; D042461:Vascular Endothelial Growth Factor A; D042643:Vascular Endothelial Growth Factor D; D040301:Vascular Endothelial Growth Factor Receptor-2; D000099175:Heparanase; C467480:vascular endothelial growth factor A, mouse; C501830:Mmp9 protein, mouse